Ovarian cancer is a major contributor to cancer moralities worldwide and is the fifth most common cause of cancer death in Australian women, with approximately 1200 new cases diagnosed and 750 deaths each year (Australian Institute of Health and Welfare, 2002). It is an insidious disease with no specific symptoms and currently no accurate screening test. Consequently, ovarian cancer is usually not diagnosed until extensive spread has occurred. Ovarian cancers show a high response rate to chemotherapy, but unfortunately this does not translate to high cure rates. Indeed, although chemotherapy has increased survival times, there has been little improvement in cure rate, with only 20% of patients with advanced stage ovarian cancer surviving more than 5 years (Kricker, 2002). There is a need for improved therapies for the treatment of advanced ovarian cancer.
Platinum-based drugs including cisplatin and its analogues carboplatin and oxaliplatin, are commonly used chemotherapeutic agents that are effective as single agents or in combination with other drugs in the treatment of a wide variety of malignant solid tumours including germ cell tumours, and cancers arising in lung, upper aero-digestive tract, urothelium as well as the ovarian epithelium. However not all patients respond equally to these drugs (for example approximately 30% of ovarian cancers do not respond) and some patients that do respond to initial treatment subsequently develop resistance to the drugs and do not respond when their disease relapses. Accordingly, there is an urgent need for the development of new therapeutic and management strategies for cancers resistant to chemotherapeutic drugs. Progress in this regard requires improved understanding of the molecular and genetic changes that result in resistance to chemotherapy.
A number of genes have been implicated in resistance to platinum-based chemotherapy. For example demethylation of one of the key genes in the Fanconi anaemia-BRCA1 pathway, FANCF, has been shown to result in increased cisplatin resistance (Taniguchi et al., 2003). At the level of transmembrane transport, there is also evidence that the transmembrane transport protein MRP2, is a platinum export pump and that lack of expression increases platinum sensitivity (Guminski et al., 2005). In addition, the induction of TP53 expression following DNA strand breaks leads to apoptosis and also contributes to cisplatin cytotoxicity (Niedner et al., 2001). However it is not yet possible to predict sensitivity to platinum-based drugs in patients, nor to design rational strategies to overcome resistance. The ability to predict drug response would assist in identifying those patients that fail to respond to therapy without significant benefit, thereby enabling the early selection of a potentially more effective chemotherapy regime. Similarly, a detailed understanding of the pathways involved in the determination of drug sensitivity will lead to novel, targeted strategies for overcoming resistance.
Despite the lack of detailed understanding of the mechanisms that underlie clinical drug tumour resistance, targets have been implicated and clinical trials initiated. These include co-administration of inhibitors of p-glycoprotein and MRP1 drug efflux pumps; however no increase in response rates have been seen in trials conducted thus far. Detailed understanding of the pathways and underlying mechanisms involved in chemotherapeutic response is clearly required to maximize the likelihood of success of these types of approaches.
Further, despite the number of drug-resistance mechanisms that have been described in vitro, to date none of these mechanisms has been shown unequivocally to be important in the clinical setting. This can be attributed to some extent to the models used to study drug resistance. In many studies, sensitive cell lines have been exposed to increasing doses of cytotoxic drugs to generate resistant cell lines and as a consequence cell lines with several-hundred-fold greater resistance to the drug have been generated. However, the clinical relevance of resistance mechanisms generated by such methods has been questioned (Agarwal and Kaye, 2003). In clinical practice, tumours are exposed to repeated fixed drug concentrations and this could select for resistance via different mechanisms. These observations support the need for further searches for genes and pathways that might be clinically useful determinants of tumour response to chemotherapy.
The present invention is predicated on the inventors' finding that the muscle ankyrin repeat protein ANKRD1 (ankyrin repeat domain 1 (cardiac muscle) protein) also known as CARP, is expressed in human ovarian and breast tumours and that alterations in the level of expression of ANKRD1 modulates the sensitivity of the tumour cells to cisplatin.